Preparation of 7-acylamido-7-methoxy-3-substituted methyl-3(or 2)-cephem-4-carboxylic acid and its s-oxides

ABSTRACT

A process for preparing 7-acylamido-7-methoxy-3-substituted methyl-3(or 2)-cephem-4-carboxylic acid and its S-oxide and its salts, esters and amides which comprises treating 7-acylamido-7methoxy-3-methyl-3(or 2)-cephem-4-carboxylic acid and its S-oxide or the salts or ester derivatives thereof with a reagent capable of replacing a hydrogen atom of the 3-methyl radical with a halo, hydroxy or lower alkanoyloxy radical. The products are either antibiotics or are useful intermediates in the preparation of antibiotics.

United States Patent [191 Pines [4 1 Feb. 18,1975

[541' PREPARATION or 7-ACYLAMlD0-7-METHOXY-3- SUBSTITUTED METHYL-3(OR2)-CEPHEM-4-CARBOXYLIC ACID AND ITS S-OXIDES [75] Inventor: Seemon H.Pines, Murray Hill, NJ.

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Dec. 14, 1971 [21] Appl. No: 207,980

[52] U.S. Cl. 260/243 C, 424/246 [5 ll Int. Cl C07d 99/24 H81 Field ofSearch 260/243 C [56] References Cited UNITED STATES PATENTS 2.964.559l2/l960 Burney 260/525 3.6825903 8/1972 Bickel ct al. 260/243 C OTHERPUBLICATIONS D E. Burney et al., Chemical Abstracts, Vol. 53, p. 19 957b, (1959).

Primary ExaminerDonald G. Daus Assistant Examiner-Jose Tovar Attorney,Agent, or FirmWalter Patton; Julian S. Levitt; J. Jerome Behan ABSTRACTA process for preparing 7-acylamido-7-methoxy-3- substituted methyl-3(or2)-cephem-4-carboxylic acid and its S-oxide and its salts, esters andamides which comprises treating 7-acylamido-7-methoxy-3-methyl- 3(or2)-cephem-4-ca rboxylic acid and its S-oxide or the salts or esterderivatives thereof with a reagent capable of replacing a hydrogen atomof the 3-methyl radical with a halo, hydroxy or lower alkanoyloxyradical. The products are either antibiotics or are useful intermediatesin the preparation of antibiotics.

4 Claims, N0 Drawings PREPARATION OF 7-ACYLAMIDO-7-METHOXY-3-SUBSTITUTEDE H L-M ):.CERHEM-4:C. RQ

ADTD AND ITS S-OXIDES This invention is directed to a novel process forpreparing 7-acylamido-7-methoxy-3-substituted. methyl- 3(or2)-cephem-4-carboxylic acid and its S-oxides (l) and the nontoxic,pharmaceutically acceptable salts. esters and amide derivatives thereofby treating the corresponding 7-acylamido-7-methoxy-3-methyl-3(or2)-cephem-4-carboxylic acid (H) or its S-oxide with a reagent capable ofreplacing a hydrogen atom of the 3-methyl radical with a halo, hydroxyor lower alkanoyloxy radical. Some of the 7-acylamido-7-methoxy-Sl-substituted methyl3-cephem-4-carboxylic acids and theirsalts, esters and amide derivatives obtained in this process are usefulas antibiotics whereas other compounds prepared by this process providea convenient starting material for preparing other cephalosporinssubstituted in the .T-positibn by various other radicals.

l'hose ccphalosporin compounds having a 7-methoxy substituent exhibitantibacterial properties similar to the known ccphalosporin compounds.However, the 7-methoxy substituted compounds exhibit a broader spectrumof activity.

Cephalosporins having a 7-methoxy substituent are effected against gramnegative bacteria including Escherichia C, Proteus vulgaris, Proteusmirabilis, Proteus morganii, Salmonella schorrmuelleri, Klebsiellapneumoniue AD, Klebsiella pneumoniae B, and Paracolobactrum arizoniaeand gram positive bacteria including Staphylococcus aureus,Streptococcus pyogcnes and Diplococc'us pneumoniae.

The cephalosporins are useful in removing susceptible microorganismsfrom pharmaceutical, medical and dental equipment and as bactericides inindustrial applications, for example, in water based paints and in thewhite water of paper mills to inhibit the growth of harmful bacteria.

The instant process comprises a novel process for the t'unctionalizationof the 3-methyl radical of the recently discovered 7-methoxycephalosporins. In general, the process is an oxidation, i.e., theprocess involves a removal of a hydrogen from the methyl radical.Naturally, the particular function which can be inserted at the 3-methylposition depends on the nature of the particular reagent employed.

This novel process comprises treating an ester of a'l-acylamido-7-methoxy-3-methyl-3(or 2)-cephem-4- carboxylic acid or itsS-oxide with a reagent capable of replacing a hydrogen on the 3-methylgroupselected from: (1) a halogenating agent such as N-bromosuccinimide, N-bromoacetamide, N- chlorosuccinimide ordibromodimethylhydantoin in the presence of a peroxide such as benzoylperoxide, tert-butyl peroxide. m-chloro perbenzoic acid and the like or2,2 '-azobisisobutyronitrile in a suitable inert solvent, for example,halogenated alkanes such as chloroform, carbon tetrachloride,dichloromethane, tetrachloroethane and the like or aromatic hydrocarbonssuch as benzene, chlorobenzene and the like at a temperature in therange of from about room temperature to about |C.; (2) selenium dioxidein the presence of a lower alkanol such as ethanol. propanol and thelike. a lower alkanoic acid such as acetic acid, propionic acid and thelike or in another solvent such as diabout C. The following equationillustrates this pro- CCSSI wherein R is an'acyl radical, for example,an aliphatic, aromatic, hetcrocyclic, araliphatic or hetcrocyclicaliphatic cuboxylic acid radical of the formula:

R R CHC.

R is a blocking group and X is halo such as bromo, chloro and the like,hydroxy or lower alkanoyloxy such as acetoxy, propionyloxy and the like.

The dotted line in formulas l and Il indicates that the double bond isin either the A or A position. When the reagent employed is ahalogenating agent the starting compound II is preferably the A sulfideor A sulfoxide.

The specific reagent which is to be employed in the reaction with the3-methyl compound naturally depends upon which X group is desired. Also,it should be noted that the choice of solvents influences the nature ofthe X group which will be obtained.

The following table indicates which reagent and solvent to be employedto obtain the desired X group.

Reagent Solvent X l) Halogenating Agent Halogenated Alkanc Halo orAromatic hydrocarbons 2) Selenium Dioxide Lower alkanol Hydroxy 3)Selenium Dioxide Ether type Hydroxy 3) Selenium Dioxide Lower alkanoicAcid Lower alkanoyloxy 4) Heavy Metal Acetate Acetic Acid Acetoxy Thosecompounds wherein the acyl radical is of the formula:

0 Ra es!- wherein R and R are as defined below, represent a preferredgroup of radicals because of the generally enhanced antibiotic activityof the A compounds containing these radicals. R represents hydrogen,halo, amino, hydroxy, tetrazolyl or carboxy. R represents phenyl,substituted phenyl, a 5- or 6-membered monocyclic heterocyclc containingone or more oxygen, sulfur or nitrogen hetero atoms in the ring such asfuryl, thienyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl andthe like, substituted heterocycles, phenylthio, heterocyclic orsubstituted heterocyclic thio groups or cyano. The substituents can behalo, carboxymethyl, amibutylcarbonyloxy and the like. These estergroups may nomethyl, nitro, methoxy or methyl. Especially prebe removedby various methods, for example, the benzferred are those acyl radicalswhere R 'is hydrogen, hydryl or phenylalkyl may be removed byhydrogenaamino or carboxy and R is phenyl or a 5- or 6- tion in thepresence ofa catalyst such as palladium-onmembered heterocyclic ringcontaining from 1 to 2 sul- 5 carbon or y treatment ith a Strong organicor inorfur, oxygen or nitrogen atoms. Examples of these pregenie a id-The tert-butyl or methoxymethyl groups ferred radicals are phenylacetyl.3-bromophenylacetyl, y o be removed by treatment with a strong ori h l hl l 4- b h l h l ganlc or inorganic acid. Examples of these acids arehycetyl, 2-f l l, S i f I L 3 f l t drochloric acid, sulfuric acid,boron trifluoride ether- 5-chlorothienylacetyl, S-methoxythienylacetyl,3- ate, formic acid, trifluoroacetic acid, trichloroaceticthienylacetyl, 4-methylthienylacetyl, 3- acid, nitrobenzoic acid and thelike. isothiazolylacetyl, 4-methoxyisothiazolylacetyl, 4- When the3-methyl, A sulfoxides (llrl, infra) are isothiazolylacetyl,3-methylisothiazolylacetyl, p oyed they may be reduced to thecorrespondingly isothiazolylacetyl, 3-chloroisothiazolylacetyl, 3-substituted A sulfides (la, infra) by treatment with amethyl-l,2,5-oxadiazolylacetyl, 1,2,5-thiadiazolyl-4- l5 reducing agentsuch as stannous chloride in the presacetyl,3-methyl-l,2,5-thiadiazolyl-4-acetyl, 3-chloroence of a lower alkanoylhalide such as acetyl chloride l,2,5-thiadiazolyl-4acetyl,3-methoxy-l,2,5-thiadiazoand the like employing a suitable inert solventsuch as lyl-4-acetyl, phenylthioacetyl, 4-pyridylthioacetyl,cyaacetonitrile, dimethylformamide and the like. The renoacetyl,tetrazolylacetyl, a-fluorophenylacetyl, D- action is generally conductedat a temperature in the phenylglycyl, 4-hydroxy-D-phenylglycyl, 2 rangeof from about 0 up to about C. The following thienylglycyl,3-thienylglycyl, phenylmalonyl, 3- equation illustrates this process:

0 oca g CH S RNH RNH Reducing N HZX O/' N CHZX fi-OR IC--OR O 0 11a Iachlorophenylmalonyl, 2-thienylmalonyl, 3- wherein R, R and X are asdefined above. thienylmalonyl, a-hydroxyphenylacetyl and oz-tet- Whenthe A sulfoxides (llb, infra) are employed they razolylphenylacetyl. Anespecially preferred substitucan be Con erted to he CorrespondingAi-sulfoxide ent is Z-thienylacetyl. compound (lla, infra) by treatingthe A sulfoxide (llb) ln carrying out this reaction the 4-carb0xy groupand with an isomerizing agent, for example, an alcohol such othercarboxy, amino or hydroxy groups in the nucleus as methanol and the likeor an organic base or an absorare preferably protected with an estergroup (R in the 40 bent such as aluminum, silica gel and the like andthen formulas), for example, as ester group selected from treating the Asulfoxide (Ila) with a reducing agent, as trichloroethyl. tert-butyl,benzoylmethyl, pdescribed above, to obtain the desired 7-acylamido-7-methoxyhenzyl, benzyl, benzhydryl, trimethylsilyl,memethoxy-3-cephem-4-carboxylic acid ester (la). The thoxymethyl,benzoylmethylcarbonyloxy, tertfollowing equation illustrates thisprocess:

0 0on E 0on I] RN'H- Isomerizing RNH..

Q 0 0 ll ca x C-OR IIb IIa Reducing Agent cs S mm N o crux l(foa whereinR, R and X are as defined above.

The preparation of the 7-acylamido-7-methoxy-2- (and3)-cephem-4-carboxylic acids and its corresponding S-oxide and theesters thereof is described in U.S. application Ser. No. 162,703,Theresa Y. Cheng, Sandor Karady, Seemon H. Pines and Meyer Sletzingerfiled July 14, 1971.

Included within the scope of this invention are the non-toxic,pharmaceutically acceptable salts of the instant products. In general,any base which will form a salt of the7-acylamido-7-methoxy-3-substituted methyl-3-cephem-4-carboxylic acidand whose pharmacological properties will not cause an adversephysiological effect when ingested by the body system is considered asbeing within the scope of this invention. Preferred salts are the sodiumand potassium salt derivatives.

Also include in addition to the esters described above are other esterderivatives which are prepared by conventional methods. These includethe lower alkyl esters such as methyl ester, ethyl ester and the like.

These non-toxic, pharmaceutically acceptable salts and esters of7-acylamido-7-methoxy-3-substituted methyl-3-cephem-4-carboxylic acidare the functional equivalent of the corresponding acid.

The following examples illustrated the novel process of this invention.However, the examples are illustrative only and it will be apparent tothose skilled in the art that other reagents and solvents similar tothose described in the following examples may be employed to affordsimilar results.

EXAMPLE 1 EXAMPLE 2 B,B,B-Trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxy-l-oxide To a refluxing solutionof B,,B,B-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-3-cephem-4- carboxy-l-oxide (1 g.)in chloroform (100 ml.) is added N-bromosuccinimide (0.5 g.) andtertiary butyl peroxide (0.03 g.). The reaction mixture is refluxed for3 more hours, cooled to room temperature and filtered.

oca RNH...

ll s The filtrate is washed with water and the solvent removed to affordB,B,B-trichloroethyl 7-(2- thienylacetamido)-7-methoxy-3-bromomethyl-3-cephem-4-carboxy-l-oxide.

EXAMPLE 3 B,B,fl-Trichloroethyl 7-(2-thienylacetamido-7-methoxy-3acetoxymethyl-2-cephem-4-carboxylate To a solution ofB,B,B-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-2-cephem-4- carboxylate (0.94 mg.,2 mmole) in acetic acid (10 ml.) is added selenium dioxide (0.111 g., 1mmole) keeping the reaction temperature at about 25C. The reactionmixture is stirred for 2 hours, filtered, diluted with water (30 m1.)and extracted with chloroform. The chloroform extracts are washedsuccessively with water, sodium bicarbonate and water. The solvent isremoved under vacuum to afford a residue which is chromatographed onsilica gel using chloroform and ethyl acetate (95:5) to affordsubstantially pure B,B,,B-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-2-cephem-4-carboxylate.

EXAMPLE 4 ,8,,B,B-Trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-hydroxymethyl-2-cephem-4-carboxylate To a solution ofBfifi-trichlorothyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-2-cephem-4- carboxylate (0.94 mg, 2mmole) in ethanol (10 ml.) is added selenium dioxide (0.111 g., l mmole)keeping the reaction temperature at about 25C. The reaction mixture isstirred for 2 hours, filtered, diluted with water (30 ml.) and extractedwith chloroform. The chloroform extracts are washed successively withwater, sodium bicarbonate and water. The solvent is removed under vacuumto afford a residue which is chromatographed on silica gel usingchloroform and ethyl acetate to afford substantially pureB,B,B-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-hydroxymethyl-2-cephem-4-carboxylate.

EXAMPLE 5 Benzhydryl 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate Manganese (Ill) acetate (5.0 g.) inacetic acid (60 ml.) is heated to C. under nitrogen. To the stirredsolution is added benzhydryl 7-(2-thienylacetamido)-7-methoxy-3-methyl-3-cephem-4-carboxylate (4.0 g.) and potassium bromide(0.5 g.). The solution is maintained at 70C. for about eight hours. Thereaction mixture is cooled and the manganese (ll) acetate is filteredfrom the cooled solution. The solvent is removed under vaccum to affordbenzhydryl 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylate.

By following substantially the procedure described in Examples 1-5 allof the products of this invention may be prepared. The followingequation, together with the following Table 1, indicate the startingmaterials. intermediates and final products which may be prepared bythis process:

l1 l2 Continued' Exam 1e 1 Position of N01.3 R R x m Double Bond. Method3 4o -cn( -occu 0 A Ex. 4

o o o 41 E 1 cuii- -cn ii-cb -oiicu o A Ex 4 s I E 2 3 mico cn (b i l 342 f -CH2-OCH3 OCCH3 O A EX- 4 s mno ca do i ii 3 43 Utlzttc C(CH3)3occa o A Ex. 4

S (i-0C(CH J- 3 44 @cn ca c(c1) 0 e14 0 A Ex. 4

W 1 v 3 2 4s CH2C- cu cc 3 Br 1 A Ex.

0 4 L 2 46 CH --ca(ti c1 0 A Ex. 1

cc(c24 ll 4 if -ca ccl 2 7 cH c- 2 3 V B: I o A Ex. 1

o 48 E j-cn ii- -CH oczr B l 1 A Ex 2 EXAMPLE A REDUCTION OF SULFOXIDEBenzhydryl ester of 7-methoxy-3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic Acid A solution of benzhydrylester of 7-methoxy-3- acetoxymethyl-7-(Z-thienylacetamido)-3cephem-4-carboxy-l-oxide (1.3 g.) in acetonitrile (8.0 ml.) and dimethylformamide(5.0 ml.) is stirred at 0C. To this the benzhydryl ester of7-methoxy-3-acetoxymethyl-7- (2-thienylacetamido)-3-cephem-4-carboxylicacid.

EXAMPLE B ISOMERIZATION Benzhydryl ester of7-methoxy-3-acetoxymethyl-7-(2- thienylacetamido )-3-cephem-4-carboxyl-Oxide The benzhydryl ester of 7-methoxy-3-acetoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxy-l-oxide is dissolved inmethanol (50 ml.) and the solution allowed to stand overnight to affordbenzhydryl ester of 7-methoxy-3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxy-l-oxide which is purified by column chromatography(silica gel).

EXAMPLE C DEBLOCKING 7-Methoxy-3-acetoxymethyl-7-( Z-thienylacetamido3-cephem-4-carboxylic Acid A cold solution of the benzhydryl ester of7-methoxy- 3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4- carboxylicacid (1.36 gm.) in anisole (10.88 ml. is stirred with trifluoroceticacid (5.44 ml.) at C. for /2 hour. The volatiles are removed at reducedpressure to afford substantially pure 7-methoxy-3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4carboxylic acid.

We claim: 1. A process for preparing a compound of the formula:

whcrcin R is trichloroethyl, tert-butyl, benzoylmethyl, p-methoxyhenzyl.benzyl, benzhydryl, trimethylsilyl, methoxymethyl,benzoylmethylcarbonyloxy, or tertbutylcarbonyloxy; R is hydrogen, halo,amino, hydroxy, tetrazolyl or carboxy; R is phenylthio, cyano, phenyl orsubstituted phenyl, heterocycle or substituted heterocycle, heterocyclicthio or substituted heterocyclic thio group wherein said heterocycle isselected from the group consisting of fury], thienyl, thiazolyl,isothiazolyl, oxadizolyl and thiadiazolyl, and

wherein said substituent on the phenyl, heterocycle and heterocyclicthio groups is selected from the group consisting of halo,carboxymethyl, aminomethyl, nitro, methoxy and methyl; and m is aninteger of Ol which comprises the step of treating a compound of theformula:

ide is potassium chloride or potassium iodide.

l l l =l= l

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA:
 2. The process ofclaim 1 wherein the potassium halide is potassium bromide.
 3. A processaccording to claim 1 for preparing benzhydryl7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylatewhich comprises treating benzhydryl7-(2-thienylacetamido)-7-methoxy-3-methyl-3-cephem--carboxylate withmanganese (III) acetate in the presence of potassium bromide.
 4. Theprocess of claim 1 wherein the potassium halide is potassium chloride orpotassium iodide.